In accordance with the requirements for systematic reviews and meta-analysis protocols (PRISMA-P), a topic and a research question were identified. Detailed studies were performed in the field of cocaine intoxication and cocaine metabolites directly related to the cardiovascular system and cocaine-induced cardiac pathologies. To ensure the accuracy and completeness of this systematic review, we searched for relevant scientific articles in Scopus, Web of Science, Medline, HealthCare, PubMed, PMC Europe, and Research Gate.
This study defined regular cocaine use as using cocaine at least monthly during the year prior to when the study was conducted. The study findings showed that cocaine users had higher systolic blood pressure (134 ± 11 vs. 126 ± 11 mm Hg), increased aortic stiffness, and greater LV mass (124 ± 25 vs. 105 ± 16 g) compared with cocaine non-users. Treatment for cocaine-induced acute vascular events may be similar to indications in patients with traditional risk-factors, with few exceptions. For example, enhanced supportive care and use of benzodiazepines and phentolamine for sedation; and avoiding β-blockers, which can lead to severe hyper-tension and coronary vasoconstriction resulting from the interaction of β-blockers with cocaine (for review see Ref. 13).
This process significantly increases the production of ROS and is considered to be a major mechanism of pathological changes in the entire cardiovascular system, such as cardiac ischemia-reperfusion and subsequent acute myocardial infarction 122,123. Cocaine and its metabolites are sympathomimetic agents 32 and induce local anesthetic effects 11. At low doses, cocaine-induced sympathetic effects increase heart rate, blood pressure, and myocardial contractibility, leading to increased myocardial oxygen demand 33.
- The first mechanism is the activation of the MAPK-beta-adrenergic receptor after calcium overload and subsequent phosphorylation of a multitude of calcium-containing cyclic proteins.
- When vessels are stressed, endothelin-1 (a vasoconstrictor protein produced by vascular endothelial cells) is elevated and nitric oxide (a blood vessel dilator) decreases, leading to vasoconstriction 35,36.
- Our study findings highlight the need for education regarding the deleterious effects of cocaine, and access to interventions for cocaine abusers.
- The drug transesterification in the presence of ethanol (EtOH) results in the formation of a potent pharmacologically active metabolite cocaethylene (ethylbenzoylecgonine) (Figure 2) 74,75, which shows direct cardiotoxicity, with a proven high risk of heart attack 76.
Acute ischemic heart events such as myocardial infarction, angina, SCD, etc., are life-threatening conditions with high mortality and a major reason for performing forensic autopsies 84. Studies have shown that cocaine users are also at risk of acquiring human immunodeficiency virus (HIV). Behavioral factors such as sharing needles and high-risk sexual activities can lead to transmission of HIV through blood and bodily fluids. The Centers for Disease Control and Prevention reports that about 10% of new HIV diagnoses in the United States are due to these methods of transmission (11). HIV patients who are also injection drug users experience challenges with compliance to treatment. Aside from behavioral factors, there are social barriers hindering injection drug users from seeking care.
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- For example, enhanced supportive care and use of benzodiazepines and phentolamine for sedation; and avoiding β-blockers, which can lead to severe hyper-tension and coronary vasoconstriction resulting from the interaction of β-blockers with cocaine (for review see Ref. 13).
- Cocaine and its metabolites are sympathomimetic agents 32 and induce local anesthetic effects 11.
- The cocaine molecule acts on the presynaptic transporters of monoamines and facilitates the activity of the monoamine neurotransmitters dopamine, norepinephrine (NE), and serotonin (SE) in the CNS and peripheral nervous system 1,25,26.
- Cocaine stimulates the adrenergic system by binding to norepinephrine transporters, resulting in increased norepinephrine effects at postsynaptic receptor sites.
- Based on the finding that cocaine users had a significantly higher CAA compared with cocaine non-users (30.4% vs. 7.6%, respectively), the authors concluded that cocaine users were likely to be at increased risk of acute MI.
Cocaine’s main vasoactive metabolite benzoylmethylecgonine, a tropane alkaloid, is a sodium channel blocker, which produces enhanced sympathetic activity at low doses 13,14 (Fig. 1, center box). At high doses, cocaine is markedly more dangerous than other central nervous system stimulants, including amphetamines 15, and can cause sudden cardiac death through its effect on sodium channels and local anesthetic actions 13,14,16. Cocaine crosses the blood–brain-barrier perhaps better than other psychoactive chemicals and may even induce its breakdown 17,18. In addition, cocaine blocks reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous systems, resulting in increased catecholamines, sympathetic output and stimulation 2,19. There is also evidence that the cardiovascular actions of cocaine are mediated in part by dopamine 20, via central and peripheral mechanisms 21.
Marijuana is Not Just THC
Cocaine was reported as a strong vasoconstrictor and can be detected in the blood and urine even 4 days after use. The time to peak blood concentration varies and depends on the route of administration (smoking, oral administration, nasal inhalation, and intravenous injection). When smoking or intravenously injected, the maximum concentration of the drug is reached between 1 and 5 min, and orally between 60 and 90 min 79.
Pathological Effects of THC
The main chemical reactions to cocaine that produce toxic metabolites include hydrolysis and decarboxylation. Although there is individual variability, cocaine can be detected in oral fluids for up to 24 h in urine for approximately four days, and in hair, especially in chronic use, for up to 90 days 12. This section collects any data citations, data availability statements, or supplementary materials included in this article.
One study showed that cocaine users had more plaques than non-cocaine users and concluded that cocaine users have greater development of coronary atherosclerosis (10). First, this was a study with a limited number of participants and unbalanced data (69% were chronic cocaine users and 81% were men, and 81% were HIV positive). Of note, although the chronic and non-cocaine users in this study were not matched explicitly, the groups were comparable with respect to sex, age, BMI, diabetes, and HIV status.
2. Mechanisms of Chronic Toxicity
Ecgonine can be detected 98 h after administration of cocaine in the urine 72 and up to 8 days after a single dose 73. The data set came from a longitudinal study examining the cardiovascular consequences of HIV infection and chronic cocaine use in a predominantly African American population in Baltimore, MD. The baseline data collected on the participants included demographic data, medical data, use of anti-retroviral therapy (ART), substance use, treatment history, and clinical data such as coinfections and HIV viral load. Participants also provided biological specimen samples, including urine and blood, and contrast-enhanced coronary computed tomography angiography (CCTA) data (13).
For each year increase in cocaine use, total plaque volume and total LAD plaque volume increased by 7.23 mm3 and 4.56 mm3, respectively. In summary, cocaine use affects eating behavior and suppresses appetite, leading to malnutrition and anorexia through disruption of the metabolic process and neuroendocrine regulation. Also, cocaine uptake in the body can lead to mesenteric vasoconstriction and focal tissue ischemia, and alter lipid as well as glucose profiles, presumably resulting in increased risk for metabolic and cardiovascular problems in cocaine users. Notably, the cessation of cocaine use causes sudden/excess weight gain during the recovery period/process, leading to increased cardiovascular and cardio-metabolic risks. As such, cocaine-induced changes in food intake patterns and the metabolic process can lead to cardiovascular complications during addiction as well as cessation periods. Numerous studies have also shown various physiologic mechanisms linking depression and CVD.82 One possible mechanism uses stress as a possible factor.
Mitochondria are known to be the main source of reactive oxygen, not only in cardiomyocytes but also in endothelial cells 125. Due to the presence of enzymes such as XO, NOS, and mitochondrial MAO and NAPDH oxidase, endothelial cells can also generate ROS 111. In endothelial cells with decreased xanthine dehydrogenase (XDH) levels, increased production of superoxide anion radical is induced 126.
Their combination significantly increases heart rate and can lead to myocardial depression, decreased coronary arterial blood flow, dysrhythmias, and sudden cardiac death, probably due to cocaethylene toxicity 77. Concomitant use of cocaine and nicotine significantly exacerbates the harmful effects of the drug on the heart by disrupting the supply of oxygen to the myocardium by potentiating coronary arterial vasoconstriction 78. Cocaine-induced cardiotoxicity can result in deleterious effects on the heart and vessels through multifactorial pathophysiological mechanisms, as described above. In this section, we focus on recent human studies published in the past 10 years, retrieved from the Medline database. Table 1 presents these studies that examined the association of cocaine use with both acute and chronic cardiovascular diseases and mortality.
The hydroxylamine form is a result of one step reduction process of the nitroxide and radical reduced by one electron transfer. Diamagnetic forms hydroxylamine and oxoammonium cation are not detectable with both MRI and EPR. Conceptualized and designed the study, extracted and interpreted the data, drafted the manuscript, and approved the final version of the manuscript.
Cocaine and the Heart
The study participants were 94 cocaine abusers aged 37 ± 7 years (86% male) attending a rehabilitation clinic for the first time. As previously mentioned, Kozor et al. 81 also showed greater LV mass among regular cocaine users compared with cocaine nonusers. In addition to cocaine-specific effects, there are secondary harms resulting from synergetic effects between multiple environmental, psychosocial and behavioral factors comprising the addiction phenomenology that could in turn enhance potential vascular damage. These factors include the life-course and complexity of CUD, comprised of years (often, decades) of concomitant alcohol and/or tobacco and/or other drug use, potentiating vascular toxicity. The issue is complicated further by the fact that contaminants such as procainamide, quinidine and antihistamines, which are often mixed with the cocaine, may acute and chronic effects of cocaine on cardiovascular health pmc contribute to the effects seen and influence the underlying pathophysiology 30. Furthermore, compromised decision making underlying having unprotected sex or using drugs intravenously can increase exposure to infections that activate the immune and inflammatory systems 42, potentially of additive impact in accelerating aging of the vasculature 91.